Drug interactions and the

Robert J. Herman, MD Education Abstract Éducation

DRUG INTERACTIONS COMMONLY OCCUR in patients receiving treatment with multiple . Most interactions remain unrecognized because drugs, in general, From the Department of have a wide margin of safety or because the extent of change in drug levels is small Pharmacology, College of when compared with the variation normally seen in clinical therapy. All drug inter- Medicine, University of actions have a pharmacokinetic or pharmacodynamic basis and are predictable Saskatchewan, Saskatoon, given an understanding of the pharmacology of the drugs involved. Drugs most li- Sask. able to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose–response curves; those hav- This article has been peer reviewed. ing high first-pass metabolism or those with a single, inhibitable route of elimina- CMAJ 1999;161(10):1281-6 tion. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and en- zyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interac- tions that can occur with hydroxymethylglutaryl – coenzyme A (HMG–CoA) re- ductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs.

Background

All important drug interactions, with the possible exception of idiosyncratic or allergic reactions, have a pharmacokinetic or pharmacodynamic basis, or both.1,2 Pharmacokinetic interactions refer to those where drugs or other factors cause an alteration in the concentration of unbound drug acting on the tissues. They include interactions that may lead to changes in drug absorption, drug distribution (either through binding to plasma proteins or, more importantly, binding and uptake into tissues) and drug elimination. Pharmacodynamic interactions refer to those where changes occur in tissue sensitivity or response to the same unbound drug concen- trations. The consequences of a drug interaction depend upon patient-related as well as drug-related factors (Fig. 1).3 These include the magnitude and direction of the concentration or effect changes, as well as the steepness and separation of the dose–response of the drug’s intended (therapeutic) and unintended (adverse) phar- macologic actions.1 Large changes in the concentration or tissue response to a drug possessing a flat dose–response relation or low intrinsic toxicity may be of little clinical importance. Alternatively, small changes in the concentration of potent or highly toxic drugs can be disastrous. Individual susceptibility to adverse drug effects because of health- (e.g., age, ) and disease-related factors (e.g., renal, he- patic, CNS) should also be considered. As well, the body may minimize a drug’s ef- fect through offsetting changes in tissue sensitivity, by up-regulation or down-regu- lation of receptor numbers or by changes in receptor–effector coupling, or both.4 What might produce minimal impairment on one occasion could be incapacitating on another occasion or in a less tolerant individual. Interactions between drugs binding to the same sites on plasma proteins are rarely associated with changes in drug response.1,2 The reason for this is that most of the drug exists in the body in tissue stores, mainly in muscle and fat, not in the circu- lation. Thus, even large decreases in the amount of drug bound to plasma proteins is effectively buffered by a greater distribution in peripheral tissues with little or no change in unbound concentrations. The one exception occurs with drugs possessing

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© 1999 Canadian Medical Association or its licensors Herman

small distribution volumes, like warfarin, where binding in- pathways as long as they are unencumbered. Therefore, teractions confined largely to the circulation produce large drugs that have few or minor alternative pathways are par- changes in unbound concentrations and drug effects. What ticularly prone to large concentration increases when elimi- is important to remember is that laboratories usually report nation is impaired. total drug concentrations and not unbound drug concentra- First-pass metabolism by the gut and is another im- tions. Therefore, target ranges of clinically monitored drugs portant consideration. If a drug has low oral availability due should be adjusted downwards in the presence of a binding to high presystemic elimination, there may be large in- interaction, normally with no change in dosage. Similar creases in the amount of drug getting into the body if me- considerations apply if the levels of albumin or other bind- tabolism is inhibited. Where the parent drug is inactive and ing proteins are not within the expected range. the pathway normally results in the formation of an active In contrast, displacement from tissue-based binding sites metabolite, drug response may diminish rather than in- or the inhibition of carrier-mediated uptake into tissues can crease when metabolism is inhibited.9 Conversely, response produce large changes in unbound drug concentrations.2 may be unchanged if both parent and metabolites are active Drugs and their metabolites move out of tissues as readily — increases in the concentration of the parent offset by de- as they move in, and muscle and fat often contain large creases in the metabolites.9 body stores, particularly following multiple dosing. The The mechanism of interaction is also an important fac- factors causing redistribution from tissues into the circula- tor; an interacting drug may not be a known inhibitor but tion are not well understood, although evidence suggests merely a substrate for the same metabolic pathway and that this occurs commonly with lipophilic drugs that have thereby produce only minor dose-dependent competition large distribution volumes.5 Examples of clinically relevant at the active enzyme site.10 In this case, the affinity of the interactions involving the inhibition of drug distribution substrate for the enzyme and the unbound concentration and transport include the 2- to 3-fold elevations in digoxin and half-life of the inhibiting drug are important determi- serum concentrations following the concomitant adminis- nants of the extent and time course of the interaction. Al- tration of quinidine or verapamil.6 ternatively, inhibition may be noncompetitive or uncom- The inhibition or induction of hepatic petitive, wherein the effect is likely to be more complete is a major source of variability in drug response and is the and long lasting, requiring resynthesis of new enzyme be- basis of many adverse drug interactions.7 Paramount to an fore it can be overcome.10 understanding of this is a consideration of the role of the liver in the overall elimination of the drug. Most drugs are The cytochrome P450 superfamily removed from the body through multiple competing path- ways of renal and hepatic . If one or several of Hepatic metabolism is served by a superfamily of oxyge- these become blocked because of disease or the action of nases known as the cytochrome P450s. The purpose of another drug, clearance will diminish, dependent upon the these enzymes is to add a functional group to a drug, an en- relative contribution of the affected pathway(s) to the total vironmental chemical or an endogenous molecule and, in elimination of the drug.8 If this occurs, steady-state concen- so doing, increase either its polarity and excretion from the trations and, correspondingly, drug or adverse effects rise. body or its interaction with similar enzymes. The most dis- However, these in turn drive elimination through other tinguishing characteristic of the cytochrome P450 family is its great diversity; members have a broad and overlapping substrate specificity and an ability to interact with almost any chemical species. The superfamily, referred to as the CYP enzymes, is subdivided according to the degree of ho- mology in amino acid sequences. CYP enzymes possessing more than 40% homology are grouped together into fami- lies, which are designated by an Arabic numeral (e.g., the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (e.g., CYP2C and CYP2D subfamilies); members of each sub- family have more than 55% homology with one another. Finally, individual members are given an additional number (e.g., CYP3A4) to identify a specific enzyme pathway. Over 70 CYP families have been identified to date, of which 14 are known to occur in all mammals.11 Of the 26 mammalian subfamilies, the CYP2C, CYP2D and CYP3A subfamilies are involved in the metabolism of most clinically relevant Fig. 1: Factors influencing drug interactions. (Adapted from drugs. Important substrates, inducers and inhibitors of the Hansten).3 major CYP enzymes are listed in Table 1.

1282 JAMC • 16 NOV. 1999; 161 (10) Drug interactions

The CYP2C subfamily comprises about 20% of all of CYP2C isozymes have been characterized, each having the cytochrome P450s in the liver.12 At least 6 different greater than 80% homology with distinct but overlapping

Table 1: Inducers and inhibitors of major CYP enzymes Enzyme; substrate Enzyme inducers Enzyme inhibitors

CYP1A2 TCAs , lansoprazole Fluvoxamine (other SSRIs weak) Haloperidol, olanzapine , , Ciprofloxacin (other quinolones weak) Propranolol, local anesthetics , , rifampin Cimetidine Theophylline, caffeine Cigarette smoke Isoniazid Diazepam, chlordiazepoxide Oral contraceptives Estrogens, tamoxifen Insulin Ticlopidine CYP2C9 ASA and most NSAIDs Rifampin Fluvoxamine (other SSRIs weak) Phenobarbital, phenytoin Phenobarbital, phenytoin, carbamazepine S-Warfarin, dicumarol Omeprazole (activation) Ritonavir Tolbutamide, sulfonamides, dapsone HMG-CoA reductase inhibitors Zidovudine Tolbutamide Diazepam, temazepam Cimetidine (weak) Fluoxetine, meclobemide Azole (weak) CYP2C19 TCAs Rifampin Fluoxetine, fluvoxamine, paroxetine Diazepam, temazepam Phenobarbital, phenytoin, carbamazepine Omeprazole, lansoprazole Omeprazole, lansoprazole Prednisone Ritonavir Propranolol Norethindrone Azole antifungals (weak) Phenytoin, barbiturates, valproic acid Cimetidine (weak) Zidovudine Ticlopidine CYP2D6 TCAs, SSRIs, venlafaxine Quinidine Phenothiazines, haloperidol Fluoxetine, paroxetine, sertraline Several β-blockers TCAs, venlafaxine Codeine, oxycodone, hydrocodone Phenothiazines, haloperidol, Dextromethorphan Omeprazole Cimetidine Halothane Ritonavir MDMA (ecstasy) HMG-CoA reductase inhibitors Encainide, flecainide, propafenone Amiodarone, encainide Selegiline Chlorpheniramine CYP2E1 Acetaminophen Ethanol Disulfiram Ethanol and other alcohols Isoniazid Ethanol Inhalational anesthetics Cimetidine Sulfonamides, dapsone Isoniazid CYP3A4 Halothane Phenytoin, barbiturates Ketoconazole, , fluconazole , alfentanil, sufentanil Rifampin Erythromycin, clarithromycin TCAs, SSRIs Erythromycin TCAs, nefazodone, venlafaxine Erythromycin, clarithromycin Omeprazole, lansoprazole Fluvoxamine, fluoxetine, sertraline HIV protease inhibitors , sex steroids Cyclosporine, Calcium-channel blockers (not diltiazem) Omeprazole, lansoprazole Lovastatin, , Calcium-channel blockers (esp. diltiazem) Cyclosporine Midazolam Terfenadine, astemizole, Corticosteroids Midazolam, alprazolam, triazolam juice Cisapride Tamoxifen

Note: TCA = tricyclic antidepressant, SSRI = selective serotonin reuptake inhibitor, HMG–CoA = hydroxymethylglutaryl – coenzyme A.

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substrate specificity. Prostaglandins and sex steroids are im- and are known to be responsible for many drug interac- portant endogenous substrates of the CYP2C subfamily. tions.10,15 Terfenadine, astemizole, cisapride, cyclosporine The most abundant enzyme in this subfamily, CYP2C9, is and many of the hydroxymethylglutaryl – coenzyme A responsible for the breakdown of a number of drugs in- (HMG–CoA) reductase inhibitors are potentially toxic cluding ASA and many of the nonsteroidal anti-inflamma- drugs or drugs susceptible to large changes in concentra- tory drugs, sulfonamides, phenytoin and S-warfarin (the tion following enzyme inhibition and, therefore, are candi- more active enantiomer of warfarin). CYP2C19 is involved dates for serious interactions with other substrates of in the metabolism of diazepam, omeprazole and the tri- CYP3A4.10 These interactions can have serious clinical cyclic antidepressants. Both CYP2C9 and CYP2C19 are consequences. polymorphic, meaning the expression of these enzymes is under strong genetic influence and some individuals have Interactions with HMG–CoA reductase markedly deficient activities. Indeed, 3% of white people and 20% of all those of Japanese descent lack CYP2C19 inhibitors and are unable to metabolize diazepam and omeprazole by the usual pathways.13,14 However, since many of the en- The HMG–CoA reductase inhibitors (statins) are associ- zymes in this family have overlapping substrate specificities, ated with 2 uncommon but important side effects, namely it is unusual to see excessive or adverse drug effects even in asymptomatic elevation in liver enzymes and skeletal muscle people completely deficient in CYP2C19.15 Serious interac- abnormalities, which can range from benign to my- tions occur predominantly with drugs that have a low ther- opathy (10-fold elevation in with muscle pain apeutic index such as warfarin or phenytoin.10 or weakness) and life-threatening .19,20 The CYP2D6 accounts for only 4% of hepatic CYP en- incidence of in patients taking statins alone is esti- zymes,12 but is more unique in its metabolic profile. Impor- mated to be 0.1%–0.2%,20,21 and rhabdomyolysis is exceed- tant substrates for this enzyme include tricyclic antidepres- ingly rare. Evidence suggests that myopathy is a direct con- sants, selective serotonin reuptake inhibitors, neuroleptics, sequence of HMG–CoA reductase inhibition22,23 and is opioid analgesics and several of the β-adrenergic blockers. dose-dependent.24–27 Myopathy is most likely to occur when Seven to 10% of white people and 3% of black and oriental statins are administered with other drugs or chemicals that people are known to be deficient in the CYP2D6 enzyme, are themselves myotoxic or that elevate the concentrations of the so-called sparteine–debrisequine, poor metabolizer the to the toxic range. Indeed, the incidence of muscle polymorph.13,14 These individuals show great variability in disorders increases over 10-fold when statins are given with clinical response (up to 1000-fold) and commonly have ad- ,20,28–31 ,20,32 erythromycin,33 itraconazole,34,35 verse effects to standard doses of drugs metabolized by this cyclosporine,20,36,37 and diltiazem38 among others. enzyme. Also, they are unable to convert codeine, oxy- Six statins are currently marketed for the treatment of codone and hydrocodone to their active metabolites16 and in North America. Lovastatin, simvastatin, thereby derive little or no analgesic benefit from oral mor- atorvastatin and are all substrates of phine analogues. Levels of CYP2D6 are not affected by CYP3A439–41 and would be subject to marked inhibition of age, sex or smoking status.17 Inhibitors are quinidine, keto- metabolism by azole agents, macrolide antibi- conazole and most antidepressants and neuroleptics, and otics, selective serotonin reuptake inhibitors, cyclosporine, there are no known inducers of this enzyme. diltiazem and grapefruit juice. is metabolized by The CYP3A subfamily, like CYP2D6, is involved in the CYP2C9; it would not be affected by these substrates, but metabolism of a large number drugs and other chemicals rather would have a different spectrum of interactions,32,42 and is involved in many drug–drug and drug–food interac- perhaps less clinically relevant because of the overlap be- tions. It is the most abundant of all of the P450s in the hu- tween CYP2C isozymes. is not significantly man liver (25%–28%, but sometimes as high as 70%) and metabolized by CYP and would be comparatively devoid of is widely expressed throughout the , these effects.43,44 Lovastatin, simvastatin and atorvastatin are kidneys and lungs.12 More than 150 drugs are known sub- all extensively metabolized on first-pass through the strates of CYP3A4, the major CYP3A isozyme, including liver39,40,45 with resultant low oral availability (5%–10%), many of the opiate analgesics, steroids, antiarrhythmic whereas cerivastatin has an intermediate availability of agents, tricyclic antidepressants, calcium-channel blockers around 60%.46 Moreover, the active CYP3A metabolites of and macrolide antibiotics. Although several substrates show atorvastatin and cerivastatin contribute in large measure to age-dependent reductions in elimination, the enzyme itself their overall clinical activity.40,46 Thus, inhibition of first- does not appear to be altered.18 Also, sex-related effects are pass metabolism of lovastatin or simvastatin could result in small and probably not important. Ketoconazole, itracona- 10–20 fold elevations (oral availability increasing from 5% zole, erythromycin, clarithromycin, diltiazem, fluvoxamine, to 100%) in steady-state concentrations with a marked lia- fluoxetine, nefazodone, cyclosporine and dihydroxyberg- bility to drug toxicity. Inhibition of metabolism of atorvas- amottin and various substances found in grapefruit juice, tatin and cerivastatin, on the other hand, is likely to pro- green tea and other foods are potent inhibitors of CYP3A4 duce a balanced inhibition with small changes in the total

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active drug concentration within the normal dosing range. This work was supported by an educational grant from Bristol- Indeed, pharmacokinetic interactions of these types have Myers Squibb. Bristol-Myers Squibb had no control over the been confirmed recently for each of the marketed content of this manuscript. statins.47–53 Competing interests: Dr. Herman received speaker fees from A MEDLINE review of all interactions involving a Bristol-Myers Squibb. statin and any other drug between 1984 and 1999 revealed 1 case report of rhabdomyolysis in a patient receiving References pravastatin and , but 27 cases of rhabdomyolysis in patients on simvastatin combined with either gemfi- 1. Nies AS, Spielberg SP. Principles of therapeutics. In: Hardman JG, Limbird brozil, nefazodone, cyclosporine, itraconazole or mibefradil LE, Molinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. and 37 cases in those on lovastatin plus gemfibrozil, niacin, p. 43-62. cyclosporine, itraconazole or erythromycin (references 2. Roland M, Tozer TN. Interacting drugs. In: Roland M, Tozer TN, editors. Clinical . 2nd ed. Philadelphia: Lea and Febiger; 1989. p. 255-75. available on request). There are numerous other reports 3. Hansten PD. Understanding drug–drug interactions. Science & Medicine documenting lesser degrees of myopathy, and 1998;5(1):16-25. 4. Ross EM. Mechanisms of drug action and the relationship between drug con- asymptomatic elevations in creatine kinase showing the centration and effect. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon same pattern of predilection for lovastatin and simvastatin. RW, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of However, the mere potential for a drug interaction to oc- therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 29-42. 5. Pounder DJ, Hartley AK, Watmough PJ. Postmortem redistribution and cur, even its citation in the literature, provides little indica- degradation of dothiepin. Human case studies and an animal model. Am J tion of the true incidence of adverse outcomes in routine Forensic Med Pathol 1994;15:231-5. 6. Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of clinical use. Monotherapy with lovastatin, pravastatin and P-glycoprotein-mediated drug transport: a unifying mechanism to explain the simvastatin has a proven record of safety and efficacy in interaction between digoxin and quinidine. Circulation 1999;99:552-7. 21,54,55 7. Roland M, Tozer TN. Variability. In: Roland M, Tozer TN, editors. Clinical large clinical trials. Moreover, there are numerous re- pharmacokinetics. 2nd ed. Philadelphia: Lea and Febiger; 1989. p. 197-212. ports in the recent literature documenting the safe use of 8. Herman RJ, Szakacs CBN, Verbeeck RK. Analysis of polymorphic variation in drug metabolism: II. Effects of data transformation on the sensitivity and low dose statin–cyclosporine and statin– combina- specificity of modal detection. Clin Invest Med 1994;17:290-6. tions in high-risk patients or patients with complex dyslipi- 9. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the 56,57 likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet demias (other references available on request). Indeed, 1997;32:210-58. patients who experienced serious toxicity often received 10. Michalets EL. Update: clinically significant cytochrome P-450 drug interac- other drugs, in addition to the interacting drug cited, that tions. Pharmacotherapy 1998;18:84-112. 11. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman competed with the statin through CYP3A4. DJ, et al. P450 superfamily: update on new sequences, gene mapping, acces- Finally, the interaction of the statins with the fibric acid sion numbers and nomenclature. Pharmacogenetics 1996;6:1-42. 12. Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report lipid-lowering agents like gemfibrozil and fenofibrate is summarizing their reactions, substrates, inducers and inhibitors. Drug Metab thought to have a pharmacodynamic rather than a pharma- Rev 1997;29:413-580. 13. Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano cokinetic basis. Although rhabdomyolysis has been re- PR, editor. Cytochrome P450 — structure, mechanism and biochemistry. 2nd ed. ported most frequently with lovastatin–fibrate combina- New York: Plenum Press; 1995. p. 473-535. 14. Spatzeneger M, Jaeger W. Hepatic P450 in drug metabolism. Drug Metab Rev tions, there have also been cases reported with each of the 1995;27:397-417. other marketed statins, except possibly cerivastatin. Studies 15. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical im- have not found any fibrate-dependent alterations in statin plications. Am Fam Physician 1998;57:107-16. 16. Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine o-demethylation 28,58 concentrations, however. Moreover, statin-induced my- co-segregates with polymorphic debrisequine hydroxylation. Br J Clin Phar- opathy is seen with hypothyroidism59–61 or congenital or macol 1989;28:639-45. 62,63 17. Ozdemir V, Fourie J, Busto U, Naranjo CA. Pharmacokinetic changes in the acquired myopathic conditions. This drug–disease inter- elderly. Do they contribute to drug abuse and dependence? Clin Pharma- action likely represents a statin-related functional mito- cokinet 1996;31:372-85. 18. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activ- chondrial deficit in addition to an inherent tendency to- ity of human hepatic CYP3A. Biochem Pharmacol 1992;44:275-83. ward muscular disease. 19. Grundy SM. HMG–CoA reductase inhibitors for treatment of hypercholes- terolemia. N Engl J Med 1988;319:24-33. 20. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Summary Cardiol 1988;62:28J-34J. 21. Pedersen TR, Berg K, Cook TJ, Faergeman O, Haghfelt T, Kjekshus J, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in Drug interactions commonly occur in patients taking the Scandinavian simvastatin survival study. Arch Intern Med 1996; 156:2085-92. multiple medications. Although there may be some differ- 22. Hrab RV, Hartman HA, Cox RH Jr. Prevention of fluvastatin-induced toxic- ity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid sup- ences in the potential for statin preparations to be involved plementation. Teratology 1994;50:19-26. in serious adverse drug reactions, in general, they have a 23. Flint OP, Masters BA, Gregg RE, Durham SK. HMG–CoA reductase in- hibitor-induced myotoxicity: pravastatin and lovastatin inhibit the geranylger- proven record of safety and efficacy in large clinical studies. anylation of low-molecular-weight proteins in neonatal rat muscle culture. Nonetheless, concern is warranted when statins, particu- Toxicol Appl Pharmacol 1997;145:99-110. 24. Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated larly lovastatin and simvastatin, are used in multidrug regi- muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol 1995;27:2397-402. mens because of dose-dependent toxicity and their propen- 25. Smith PF, Eydelloth RS, Grossman SJ, Stubbs RJ, Schwartz MS, Germer- shausen JI, et al. HMG–CoA reductase inhibitor-induced myopathy in the sity toward marked elevations in concentration if taken rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther with drugs that inhibit first-pass metabolism. 1991;257:1225-35.

CMAJ • NOV. 16, 1999; 161 (10) 1285 Herman

26. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp 56. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and ef- RH, et al. The efficacy and 6-week tolerability of simvastatin 80 and 160 ficacy of HMG–CoA reductase inhibitor monotherapy in the treatment of mg/day. Am J Cardiol 1997;79:38-42. primary . Ann Pharmacother 1995;29:743-59. 27. Nakai A, Nishikata M, Uchida T, Ichikawa M, Matsuyama K. Enhanced my- 57. Ballantyne CM, Bourge RC, Domalik LJ, Eisen HJ, Fishbein DP, Kubo SH, opathy following administration of hypolipidemic agents under urethane et al. Treatment of hyperlipidemia after heart transplantation and rationale anesthesia. Biol Pharm Bull 1997;20:104-6. for the heart transplant lipid registry. J Am Coll Cardiol 1996;78:532-5. 28. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associ- 58. Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE. Pharmacoki- ated with lovastatin-gemfibrozil combination therapy. JAMA 1990;264:71-5. netics of the combination of fluvastatin and gemfibrozil. Am J Cardiol 29. Abdul-Ghaffar NU, el-Sonbaty MR. Pancreatitis and rhabdomyolysis associ- 1995;76:80A-83A. ated with lovastatin–gemfibrozil therapy. J Gastroenterol 1995;21:340-1. 59. Scalvini T, Marocolo D, Cerudelli B, Sleiman I, Balestrieri GP, Giustina G. 30. Van Puijenbroek EP, Du Buf-Vereijken PWG, Spooren PFMJ, van Door- Pravastatin-associated myopathy. Report of a case. Recenti Prog Med maal JJ. Possible increased risk of rhabdomyolysis during concomitant use of 1995;86:198-200. simvastatin and gemfibrozil. J Intern Med 1996;240:403-4. 60. Galiana J, Marchan E, Montes I, Pato S. Toxic related to the ad- 31. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvas- ministration of hypolipidemic agents: Are the drugs the only things responsi- tatin–gemfibrozil therapy. South Med J 1997;90:546-7. ble? Rev Clin Esp 1995;195:620-2. 32. Garnett WR. Interactions with hydroxymethylglutaryl–coenzyme A reductase 61. Lang JE, Wang P, Glueck CJ. Myopathy associated with lipid lowering ther- inhibitors. Am J Health Syst Pharm 1995;52:1639-45. apy in patients with previously undiagnosed or undertreated hypothyroidism. 33. Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis associated Clin Chim Acta 1996;254:65-92. with lovastatin and erythromycin use. West J Med 1991;154:213-5. 62. Hino I, Akama H, Furuya T, Ueda H, Taniguchi A, Hara M, et al. Pravas- 34. Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin tatin-induced rhabdomyolysis in a patient with mixed connective tissue dis- and the antifungal agent itraconazole. N Engl J Med 1995;333:664-5. ease. Arthritis Rheum 1996;39:1259-60. 35. Horn M. Coadministration of itraconazole with hypolipidemic agents may in- 63. Giordano N, Senesi M, Mattii G, Battisti E, Villanova M, Gennari C. duce rhabdomyolysis in healthy individuals [letter]. Arch Dermatol 1996; Polymyositis associated with simvastatin. Lancet 1997;349(9065):1600-1. 132:1254. 36. Meier C, Stey C, Brack T, Maggiorini M, Risti B, Krahenbuhl S. Rhabdomy- olysis in patients treated with simvastatin/ciclosporin: role of the hepatic P450 enzyme. Schweiz Med Wochenschr 1995;125:27-8. Reprint requests to: Dr. Robert J. Herman, Department of 37. Barclay P, O’Connell P. Clarithromycin drug interactions complicating cy- Pharmacology, University of Saskatchewan, Health Sciences closporine and simvastatin therapy [abstract]. Austral J Hosp Pharm 1996; Building, 107 Wiggins Rd., Saskatoon SK S7N 5E5; 26:180. 38. Ahmad S. Diltiazem myopathy [letter]. Am Heart J 1993;126:1494-5. fax 306 966-6220. 39. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG–CoA reductase inhibitors. Similarities and differences. Clin Pharmaco- kinetics 1997;32:403-25. 40. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and thera- peutic potential in the management of hyperlipidemias. Drugs 1997;53:828-47. 41. Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, et al. Metab- olism of cerivastatin by human liver microsomes in vitro. Characterization of ANADIAN OCIETY OF HYSICIAN XECUTIVES primary metabolic pathways and of cytochrome P450 enzymes involved. Drug C S P E Metab Dispos 1997;25:321-31. 42. Transon C, Leemann T, Vogt N, Dayer P. In vivo inhibition profile of cy- tochrome P450TB (CYP2C9) by (+/-)-fluvastatin. Clin Pharmacol Ther 1995;58:412-7. 43. Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hack- barth I, et al. Comparison of cytochrome P450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl–CoA reductase in- hibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999;27:173-9. 44. Kocarek TA, Reddy AB. Regulation of cytochrome P450 expression by in- hibitors of hydroxymethylglutaryl–coenzyme A reductase in primary cultured A society of physicians who hold positions in the rat hepatocytes and in rat liver. Drug Metab Dispos 1996;24:1197-204. management of health resources or have an interest in 45. Mauro VF. Clinical pharmacokinetics and practical applications of simvas- the management of health resources. tatin. Clin Pharmacokinet 1993;24:195-202. 46. Muck W, Ritter W, Ochmann K, Unger S, Ahr G, Wingender W, et al. Ab- OBJECTIVES OF CSPE solute and relative of the HMG–CoA reductase inhibitor cerivastatin. Int J Clin Pharmacol Ther 1997;35:255-60. • to support and develop physicians to be successful 47. Azie E, Brater DC, Becker PA, Jones DR, Hall SD. The interaction of dilti- leaders in health management azem with lovastatin and pravastatin. Clin Pharmacol Ther 1998;64:369-77. • to support physicians in their roles as managers 48. Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentra- tions of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996;60:54-61. • to provide a forum for physician executives to 49. Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the network, learn and interact pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998;46:49-53. NNUAL EETING 50. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very A M susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Phar- SHERATON CENTRE, TORONTO macol Ther 1998;63:332-41. EB 51. Neuvonen PJ, Kantola T, Kivisto KT. Effect of itraconazole on the pharma- F . 26-27, 2000 cokinetics of atorvastatin. Clin Pharmacol Ther 1998;64:58-65. 52. Yang BB, Siedlik PH, Smithers JA, Sedman AJ, Stern RH. Atorvastatin phar- FOR INFORMATION CONTACT: macokinetic interactions with other CYP3A4 substrates: erythromycin and ethinyl estradiol [abstract]. Pharm Res 1996;13:S437. Dr. Chris Carruthers 53. Muck W, Ochmann K, Rohde G, Unger S, Kuhlmann J. Influence of ery- c/o CSPE thromycin pre- and co-treatment on single-dose pharmacokinetics of the 3540 Paul Anka Dr. HMG–CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacol Ottawa ON K1V 9K8 1998;53:469-73. 54. Bradford RH, Shear CL, Chremos AN, Dujovne CA, Franklin FA, Grillo RB, email: [email protected] et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: Web site: www.cma.ca/cspe two-year efficacy and safety follow-up. Am J Cardiol 1994;74:667-73. 55. Haria M, McTavish D. Pravastatin: a reappraisal of its pharmacological prop- erties and clinical effectiveness in the management of coronary heart disease. Drugs 1997;53:299-336.

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